Control of obesity has become a problem in developed cultures, despite the specter of hunger that often dominates portions of the less technologically advanced world. The litany of less-than-successful approaches which have been used in an attempt to control excess body weight is undoubtedly familar to most. Solutions range from reduced food consumption to often indiscriminate use of pharmaceuticals designed primarily for other purposes, but which appear to have a side effect of somewhat murky mechanism to result in weight loss. In short, there remain millions of people who wish to reduce their body weight without deprivation and without risking unpleasant and perhaps unhealthy side effects.
Of course, not all weight loss is necessarily desirable. Indeed, the weight loss attributable to the chronic catabolic state, referred to as cachexia, developed in the course of infections and malignancies is a handicap to recovery and is often directly fatal. In general, however, cachexia is thought to be a normal response to infection, and is undesirable only when permitted to proceed without proper control. The catabolism is characterized by a net breakdown of lipids in adipose cells, and it has been surmised that this undesirable balance is at least in part a result of failure of the cells to synthesize adequate amounts of lipogenic enzymes.
A crude protein extract from the media of endotoxin-stimulated macrophages, designated "cachectin", has been shown to induce indicia of cachexia in tissue culture (Torti, F., et al., Science (1985) 229: 867-869), and antibodies raised against it have been shown to protect mice from some of the effects of E. coli lipopolysaccharide endotoxin (Beutler, B., et al., ibid, pp. 869-871).
It has now been shown that tumor necrosis factor (TNF) specifically alters the characteristics of adipocytes in tissue culture in a manner thought to model at least part of the cachexia process. Later work has indicated that cachectin and native TNF, which was originally obtained from the sera of endotoxin-treated mice, and which is now available in recombinant form, have the same primary structure. Accordingly, TNF is a useful material for control of weight by stimulating this catabolic reaction under controlled conditions and under circumstances where such stimulation is desirable. It is also possible to control undesirable weight loss by neutralizing TNF.